The paired helical filaments (PHFS) composing the neurofibrillary tangles have been the subject of chemical investigation for over fifteen years yet their nature still remains clouded. A method has been developed, which completely solubilizes and denatures the PHFs to make them amenable to chemical analysis. A solubilized concentrate of PHFs has been analyzed on SDS-PAGE gels and the peak PHF "core" or backbone protein fraction gives an apparent monomeric molecular weight of 35 kDa. The major protein eluted from the SDS gels and bound to a PVDF membrane is found by amino acid sequence analysis to have a blocked N-terminus. This protein was then subjected to tryptic digestion yielding 5 peptide peaks. A partial amino acid sequence of the major peptide has been obtained which fails to correspond to any known protein when compared to a sequence data bank.This investigation will provide a complete amino acid sequence of the PHF backbone protein by utilizing further chemical and enzymic cleavage to produce overlapping peptides for analysis. The PHF gene will be cloned based on these sequences. These studies and the analyses for polysaccharide and phosphate residues will determine if abnormalities in post-translational events are responsible for PHF formation. The amyloid core of senile plaques has never previously been reproducibly defined. A method employing sequentially anhydrous trifluoroacetic acid and 5.8 M guanidine isothiocyanate solubilizes a concentrate of plaques and SDS-PAGE reveals a major protein band at 6 kDa. Amino acid sequence analysis reveals a blocked N-terminus. This plaque amyloid fibril protein, which is believed to be composed of the beta protein, will be subjected to chemical and enzymic digestion in order to define its length and complete chemical composition. This analysis should reveal the cleavage sites of the beta protein precursor leading to the deposition of the plaque amyloid fibrils and aid in defining its pathogenesis.